rs2303729

Positions:

• chr19-40605163-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001042545.2(LTBP4):​c.379G>A​(p.Val127Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.457 in 1,609,426 control chromosomes in the GnomAD database, including 171,420 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (20449 hom., cov: 32)
  • Exomes 𝑓: 0.45 (150971 hom.)
• Consequence: LTBP4 NM_001042545.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.185

Genes affected

LTBP4 (HGNC:6717): (latent transforming growth factor beta binding protein 4) The protein encoded by this gene binds transforming growth factor beta (TGFB) as it is secreted and targeted to the extracellular matrix. TGFB is biologically latent after secretion and insertion into the extracellular matrix, and sheds TGFB and other proteins upon activation. Defects in this gene may be a cause of cutis laxa and severe pulmonary, gastrointestinal, and urinary abnormalities. Three transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, May 2010]

LTBP4 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.2299933E-5).
• BP6: Variant 19-40605163-G-A is Benign according to our data. Variant chr19-40605163-G-A is described in ClinVar as [Benign]. Clinvar id is 163945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-40605163-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.658 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LTBP4	NM_001042545.2	c.379G>A	p.Val127Ile	missense_variant	2/30	ENST00000396819.8	NP_001036010.1
LTBP4	NM_001042544.1	c.580G>A	p.Val194Ile	missense_variant	5/33		NP_001036009.1
LTBP4	NM_003573.2	c.469G>A	p.Val157Ile	missense_variant	5/33		NP_003564.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LTBP4	ENST00000396819.8	c.379G>A	p.Val127Ile	missense_variant	2/30	1	NM_001042545.2	ENSP00000380031.5

Frequencies

GnomAD3 genomes AF: 0.506 AC: 76876 AN: 151908 Hom.: 20415 Cov.: 32

Gnomad AFR AF: 0.664

Gnomad AMI AF: 0.385

Gnomad AMR AF: 0.381

Gnomad ASJ AF: 0.583

Gnomad EAS AF: 0.402

Gnomad SAS AF: 0.552

Gnomad FIN AF: 0.495

Gnomad MID AF: 0.487

Gnomad NFE AF: 0.443

Gnomad OTH AF: 0.473

GnomAD3 exomes AF: 0.461 AC: 110943 AN: 240400 Hom.: 26327 AF XY: 0.468 AC XY: 61174 AN XY: 130716

Gnomad AFR exome AF: 0.671

Gnomad AMR exome AF: 0.311

Gnomad ASJ exome AF: 0.581

Gnomad EAS exome AF: 0.419

Gnomad SAS exome AF: 0.559

Gnomad FIN exome AF: 0.483

Gnomad NFE exome AF: 0.445

Gnomad OTH exome AF: 0.453

GnomAD4 exome AF: 0.451 AC: 657856 AN: 1457400 Hom.: 150971 Cov.: 60 AF XY: 0.456 AC XY: 330487 AN XY: 724720

Gnomad4 AFR exome AF: 0.678

Gnomad4 AMR exome AF: 0.319

Gnomad4 ASJ exome AF: 0.575

Gnomad4 EAS exome AF: 0.371

Gnomad4 SAS exome AF: 0.557

Gnomad4 FIN exome AF: 0.486

Gnomad4 NFE exome AF: 0.438

Gnomad4 OTH exome AF: 0.478

GnomAD4 genome AF: 0.506 AC: 76965 AN: 152026 Hom.: 20449 Cov.: 32 AF XY: 0.506 AC XY: 37592 AN XY: 74296

Gnomad4 AFR AF: 0.664

Gnomad4 AMR AF: 0.381

Gnomad4 ASJ AF: 0.583

Gnomad4 EAS AF: 0.402

Gnomad4 SAS AF: 0.554

Gnomad4 FIN AF: 0.495

Gnomad4 NFE AF: 0.443

Gnomad4 OTH AF: 0.472

Alfa AF: 0.456 Hom.: 27852

Bravo AF: 0.502

TwinsUK AF: 0.442 AC: 1638

ALSPAC AF: 0.436 AC: 1682

ESP6500AA AF: 0.660 AC: 2543

ESP6500EA AF: 0.454 AC: 3739

ExAC AF: 0.465 AC: 56062

Asia WGS AF: 0.495 AC: 1722 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Feb 04, 2014	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Val194Ile in exon 5 of LTBP4: This variant is not expected to have clinical sign ificance because it has been identified in 45.4% (3739/8234) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs2303729). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 22, 2015	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.056	T;T;.
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.18	T;T;T
MetaRNN	Benign	0.000012	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.55	.;N;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.27	N;N;N
REVEL	Benign	0.17
Sift	Benign	0.18	T;T;T
Sift4G	Benign	0.18	T;T;T
Polyphen		0.0	.;B;.
Vest4		0.046
MPC		0.66
ClinPred		0.0061	T
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.025
gMVP		0.063

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2303729; hg19: chr19-41111069; COSMIC: COSV52589366; COSMIC: COSV52589366;